Pharmacogenetic Optimization of Analgesic Prescribing in Sickle Cell Disease

镰状细胞病镇痛处方的药物遗传学优化

• 批准号: 8190974
• 负责人: Cheedy Jaja
• 金额: $ 9.4万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190974
• 关键词: Absence of pain sensation; Accident and Emergency department; Acute; Acute Pain; Address; Adverse event; Advisory Committees; Algorithms; Analgesics; Biological Markers; CYP2C19 gene; CYP2C9 gene; CYP2D6 gene; Caring; Cessation of life; Clinical; Cohort Studies; Couples; Cytochrome P450; Cytochromes; Data; Development; Dose; Drug Monitoring; Drug Tolerance; Enzymes; Exposure to; Failure; Foundations; Functional disorder; Funding; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Growth and Development function; Incidence; Individual; Inherited; Intervention; Laboratories; Link; Mentored Research Scientist Development Award; Mentors; Metabolic; Mission; Modeling; Monitor; Mutation; National Institute of Nursing Research; Observational Study; Opioid; Opioid Analgesics; Outcome; Pain; Pain Disorder; Pain management; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacotherapy; Phenotype; Play; Prevalence; Principal Investigator; Publishing; Regimen; Research; Research Personnel; Research Support; Research Training; Resources; Risk; Risk Estimate; Risk Factors; Role; Scientist; Sickle Cell Anemia; Susceptibility Gene; Techniques; Testing; Therapeutic; Training; Training Programs; Translational Research; Variant; Visit; adverse outcome; authority; base; career; chronic pain; clinical practice; design; dosage; drug metabolism; experience; high risk; medical schools; mortality; programs; prospective; response; therapy design

DESCRIPTION (provided by applicant): This proposal describes a three year mentored training program for Dr. Cheedy Jaja to create a robust foundation in sickle cell disease (SCD) pharmacotherapy and analgesic pharmacogenetics essential for his transition to an independent translational research scientist with expertise in SCD pain management. A customized program of study that couples didactic coursework and research training with clinical and laboratory training in SCD pathophysiology, pain management and pharmacogenetics is designed. Dr. Abdullah Kutlar, a leading authority in SCD pain management will mentor the principal investigator's scientific growth and development, and an advisory committee of highly regarded SCD researchers and translational scientists will provide scientific and research support. The proposed mentored training draws on the excellent SCD research and clinical resources available at the Medical College of Georgia and encompasses a prospective cohort study. This study seeks to shift clinical practice by challenging the current "as-needed" opioids strategy. Although it is known to exist, the exact incidence and prevalence of suboptimal analgesic prescribing practices in SCD patients is unknown. The absence of this information is a critical barrier to progress in optimizing analgesic therapy. This proposed study approach to addressing this critical barrier is to focus on genetic polymorphisms in cytochrome P450 genes which are known to play a role in analgesic drug metabolism and could help identify patients with higher risk for therapy failure. The study is designed to test the central hypothesis that deficient cytochrome CYP2C9, CYP2C19 and CYP2D6 metabolic phenotypes and suboptimal analgesic prescribing are positively associated with ED visits in SCD patients; and to demonstrate that CYP450 phenotypes information can be used for estimating risks for repeated ED visits for analgesic therapy failure. The Tag-It Mutation Technique is used to determine CYP450 genotypes, and the Medication Quantification Scale is used to determine suboptimal prescribing incidence. The central hypothesis if confirmed, will establish deficient CYP450 phenotypes and exposure to suboptimal prescribing as clinical risk factors. The study risk prediction rules will guide clinicians in identifying individuals who would benefit from targeted, individualized intervention to reduce risks for repeated ED visits. The study will transform current clinical practice deconstructively by demonstrating that suboptimal prescribing is common in SCD analgesic therapy. Constructively, the study will establish feasibility of CYP450 phenotyping for identifying patients likely to achieve successful analgesic relief from conventional analgesic dosing regimens or patients who might benefit from analgesic switching. PUBLIC HEALTH RELEVANCE: This project addresses pain and its management with opioid analgesics in patients with sickle cell disease. By linking suboptimal prescribing of analgesics and deficiency in inherited metabolic capacity in SCD patients to frequent utilization of acute care resources, we may identify possible risk factors for poor pharmacotherapeutic outcomes in SCD patients and validate the need for genotyping to identify at-risk SCD patients for analgesic drugs failure.

描述(由申请者提供)：本建议书描述了Cheedy Jaja博士的三年指导培训计划，以在镰状细胞病(SCD)药物治疗和止痛药物遗传学方面奠定坚实的基础，这对他转变为一名具有SCD疼痛管理专业知识的独立翻译研究科学家至关重要。设计了一个定制的学习计划，将教学课程和研究培训与SCD病理生理学、疼痛管理和药物遗传学的临床和实验室培训结合起来。SCD疼痛管理领域的领先权威Abdullah Kutlar博士将指导首席研究员的科学成长和发展，一个由备受尊敬的SCD研究人员和翻译科学家组成的咨询委员会将提供科学和研究支持。拟议的指导培训利用了佐治亚医学院提供的出色的SCD研究和临床资源，并包含了一项前瞻性的队列研究。这项研究试图通过挑战目前的“按需”阿片类药物策略来改变临床实践。尽管已知存在这种情况，但SCD患者使用次佳止痛药的确切发生率和流行率尚不清楚。这些信息的缺乏是在优化止痛治疗方面取得进展的关键障碍。这项旨在解决这一关键障碍的研究方法是关注细胞色素P450基因的遗传多态性，这些基因在止痛药物代谢中发挥作用，可能有助于识别治疗失败的高风险患者。本研究旨在验证以下中心假设：细胞色素CYP2C9、CYP2C19和CYP2D6代谢表型缺陷和次优止痛药处方与SCD患者的ED就诊呈正相关；并证明CYP450表型信息可用于评估因止痛治疗失败而重复就诊ED的风险。使用Tag-It突变技术确定细胞色素P450基因分型，并使用药物量化量表确定次优处方发生率。如果中心假说得到证实，将把缺乏CYP450表型和暴露于次优处方作为临床风险因素。研究风险预测规则将指导临床医生识别将从有针对性的个性化干预中受益的个人，以降低重复急诊的风险。这项研究将解构地改变目前的临床实践，证明次优处方在SCD止痛治疗中很常见。建设性地，这项研究将建立细胞色素P450表型的可行性，以确定可能从常规止痛给药方案中获得成功止痛缓解的患者或可能从止痛药物转换中受益的患者。 公共卫生相关性：该项目涉及镰状细胞疾病患者的疼痛及其阿片类镇痛剂的管理。通过将SCD患者不理想的止痛药处方和遗传代谢能力不足与急诊护理资源的频繁使用联系起来，我们可以确定SCD患者药物治疗效果不佳的可能危险因素，并验证基因分型的必要性，以确定止痛药失效的高危SCD患者。